9alpha-halo-11beta, 21-dihydroxy-4, 17(20)-pregnadiene-3-one compounds and process of preparing thereof



i -ed, who.

.follows:

United States Patent 9oz HALO 113,21 DIHYDROXY 4,17(20) PREG- NADIENE-3-ONE COMPOUNDS AND PROCESS OF PREPARING THEREOF John A. Hogg and Frank H. Lincoln, Jr., Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan N0 Drawing. ApplicalioniDecember 17, 1954 Serial No. 476,061

53 Claims. c1. 260-23955) This invention relates :to a novel process for the production of intermediates convertible to 21-esters of 9ochalohydrocortisone, to ;a process for the production of 21-esters of 9a-halohydrocortisone, and towthe novel intermediates thus produced. r

It is an object of the present :invention to provide a process for the production of intermediates convertible to 2l-esters of, 9u-halohydrocortisone. Another object is the provision of a process for the production of 21- esters of 9u-ha1ohydrocortisone. A further object is the provision of compounds convertiblet-o 2-1-esters of 9a-halohydrocortisone. Other objects will be apparent to those skilled in the art to which this invention pertains. e a

According to the present invention, a .21-ester of 3- keto 9:11 -fi ,oxido 4,l7(20) pregnadiene 21 -ioic acid is converted to a 2l-ester of .9a-h'alohydrocortisone by the following reactions: first, cleavage of the 9:11-5- oxido group with hydrochloric acid or hydrofluoricacid to produce 3-keto-9a-halo-11/i-hydroxy-4,17(20)-pregnadiene-Zl-oieacid tester. The :,ketogroup of this latter compound is then protected with a reduction stable ketonic derivative and the compoundthen reduced with lithium aluminum hydride or other suitablekchemical carbonyl reducing agent to product a .9ti halo-11fl,21- dihydroxy-4,17(20)-pregnadiene-3 one, the ketolgroup of which is still protected :by the ketonic" derivative. Removal ofthis .ketone protectingtgroup in an appropriate manner, as by .hydrolysis, prdouces a 9a-halo- 11 3,21- dihydroxy-4,17(20)-pregnadiene-3-one. Esterification of this compound with an :acylating agentproduces the cor- 2,875,200 Patented Feb. 24, 1959 (Elia-OH 1 j a I 15 0H8 CH3 7 (BET-OH ?HaO-R" (13H no CH3 {1X I a O w 0.:

CH-OR" =0 ona I p a.

"oi V v11 40 wherein -COOR is an esterified carboxylic acid radical,

responding 9a halo I-IIlfl -hydroXy 21 acyloxy- 4,17(20.) pregnadiene --3 one. Oxidative hydroxylation of this compound with osmium .tet'roxide and an oxidizing agent produces a 21- ester of 9a-halohydrocortisone.

These reactions may be graphically exemplified as COOR Ho- T hal (heig t H-hal hsi r oi O:

hal is fluorine, chlorine, bromine or iodine, X is chlorine or fluorine,R' is a reduction stable ketonic derivative,

in this instance, illustratively exemplified as a ketal, and

,presentinvention are superior to hydrocortisone, cortisone and/or 9u-fluorohydrocortisone, .with respect to duration of activity, intensity of "activity, onset of activity, toxicity, incident of side-effects, ,or have some other modification of activity which renders ,them particularly valuable agents in a particular route of administration or in treatments requiring a particular activity pattern. a

Introduction of an oxidation step in ftl'le reactions described above, i. e1, by the oxidation of Compound VI or VII, with, for example, chromic acid, N-bromoacetamide'or N-bromosuccinimide, or other oxidizing agent which will oxidize an llfi-hydroxy group to an ll-keto group without materially affecting the other functional groups in the molecule, is ultimately productive of esters of 9oc-fll10l0 or chlorocortisone. Oxidation of a compound represented by Formula II with N- bromoacetamide, according to methods known in the art, is productive of an alkyl, e. g., methyl, 3,11-diketo- 9a-fll101'0 or chloro-4,l7(20)-pregnadiene-2l-oate. Continuing with either of these compounds through the reactions described in the chart above is productive of 9 steps 0 VIII Two steps (10 03 CH CH3 3 steps I XIII C Ha

(I) O O R CH ll 3 steps .pregnadiene-Z-l-oic acid methyl ester (XII).

4 l o For example, reacting a 3-keto-4,9(11),17(20)-pregnatriene-Zl-oic acid ester (XIII) with hypobromous acid or hypoiodous acid in the manner described hereinafter is productive of 3-keto-9a-halo-l'1[3-hydroxy-4,17(20)-pregnadiene-2l-oic acid ester (II, l1a1==Br or I), Removal of hydrogen halide from the molecule produces the corresponding 3 keto 9:11 [3 oxido 4,'l7(20) pregnadiene-Zl-oic acid ester, the starting compound of the present invention, all as disclosed more fully hereinafter.

The 3-keto-4,9(11),17 (20)-pregnatriene-2l-oic acid ester (XIII) can be prepared from lloc-hydroxyprogesterone (VIII) by monoglyoxalation with diethyl oxalate and sodium methoxide, dibromination with bromine, followed by rearrangement and elimination with sodium methoxide in methanol to produce 3-keto-l1a-hydroxy-4,17(20)- Dehydration, for example, by tosylation followed by heating with base, of XII is productive of 3-keto-4,'9(1l),l7(20)- pregnatriene-Zl-oic acid methyl ester (XIII). Alternatively, starting with 9(11)-dehydroprogesterone (IX) and performing these same reactions, with the exception of the dehydration reaction, on this starting compound, is also productive of 3-keto-4,9( 11) 17 (20) -pregnatriene-21-oic acid methyl ester. The production of 3-keto-4,9(1l), 17(20)-pregnatriene-2l-oic acid esters by this latter route is disclosed in the copending application of Hogg et al., S. N. 307,385, new U. S. Patent 2,774,776, and the compounds claimed in the copending application of Hogg et al., S. N. 476,057, filed December 17, 1954, now U. S. Patent 2,771,475.

Substituting 9: 11-;8-oxidoprogesterone (XI) for the lla-hydroxyprogesterone (VIII) as the starting steroid in the reactions described above, but eliminating the dehydration step, is productive of 3-keto-9:l1- 8-oxido-4,17- (20)-pregnatriene-2l-oic acid methyl ester (I).

Saponifying methyl 3-keto-9: 1-l-p-oxido-4,17(20) -pregnadiene-Zl-oate and reesterifying with the selected alcohol, or by ester exchange of the methyl ester, or other esterifying techniques known in the art, other esters of 3-keto-9:11-;8-oxido-4,l7(20)-pregnadiene-2l-oic acid can be prepared, especially the lower-alkyl esters, e. g., ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, heptyl, octyl.

Alternatively, 3' keto 9&11 8 oxido 4,l7(20)- pregnadie'ne-Zl-oic acid methyl ester (1) can be prepared by reacting 9:1-1-18-oxidoprogesterone (XI) with a large excess of diethyl oxalate and sodium methoxide to produce 2,2l-diethoxyoXalyl-9:lI-B-oxido-progesterone sodium dienolate. Tribrominating this compound with three molar equivalents of bromine followed by reaction with sodium methoxide and methanol is productive of 2 bromo 3 keto 9:11 [3 oxido 4,17(20) pregnadiene-Zl-oic acid methyl ester which is debrominated with zinc and acetic acid to produce 3-keto-9rl l-fl-oxido- 4,17(20)-pregnadiene-2l-oic acid methyl ester (I), all as claimed in the copending application of Hogg et al., S. N. 346,274, filed April 1, 1953, now U. S. Patent 2,790,814. An exemplary preparationof the starting compounds of the present invention (I) is shown in the preparations and the reactions of the present invention which convert this starting compound to the physiologically active esters 0g 9u-halohydrocortisone are described in detailhereina ter.

EPOXIDE OPENING The epoxide opening reaction of the present invention comprises the conversion of an alkyl ester, preferably methyl or ethyl ester, of 3-keto-9zll-fi-oxido-4,17(20)- pregnadiene-Ql-oic acid (I) to an alkyl ester of 3-keto- 9oz halo 11B hydroxy 4,17 ('20) pregnadiene 21- oic acid (II). This involves the reaction of the 9:11- ,B-oxido groupiwith hydrochloric or hydrofluoric acid to produce the 9a-chloro-11fl-hydroxy compound (II, X=Cl) and the 9a-fluoro-dlfi-hydroxy compound (II, X=F), respectively.

about plus twenty degrees centigrade.

vhowever, that optimum Theopening of a steroidal oxide with hydrochloric acid or hydrobromic acid is described by Schmidlin et al., Helv. Chim. Acta 36, 1241 (1953). Other references to such reactions include Gallagher, J. Biol. Chem. 162, 495 (1946); Cornforth et al., J. Chem. Soc. 1954, 907; and Fried et al., I. Am. Chem. Soc. 75, 2273 (1953). The latter reference reporting the opening of a steroidal oxide with hydrofluoric acid.

The 9:11-fi-oxide of Compound I when reacted with hydrofluoric or hydrochloric acid produces a 9u-halollfl-hydroxy steroid (II, hal=F, Cl). A preferred technique for the opening of the 9:11- -oxide of II involves the reaction of a solution of the oxide with anhydrous hydrogen chloride or hydrogen fluoride in an anhydrous, inert, preferably alcohol-free solvent, e. g., chloroform, methylene chloride, carbon tetrachloride, benzene, hexane, heptane, diethyl ether, acetic acid. The halogenated hydrocarbons, especially chloroform, are preferred.

Ordinarily, operating temperatures,

when employing hydrogen fluoride, are between about minus sixty and Higher temperatures, while to a certain extent operable, result in an inordinate amount of side reactions, as would be apparent to those skilled in the art. Lower temperatures are accompanied by the problems of steroid solubility and unduly long reaction times. When hydrogen chloride is employed, because of its lesser reactivity, the choice of reaction temperatures is somewhat less limited, in some instances being practical up to about plus sixty degrees centigrade. The preferred operating temperatures for either reactant is preferably below room temperature and, forhydrogen fluoride at least, below zero degrees Centigrade. 1

Reaction times required to achieve substantially complete reaction are ordinarily less than about eight hours for hydrogen fluoride and less than about 24 hours for hydrogen chloride. If a molar equivalent of the hydrogen halide is employed, the reaction time is not critical, after reaction at the oxide is substantially complete. However, when an excess of hydrogen halide is employed, particularly with hydrogen fluoride, thereaction temperature should be relatively short, e. g., less than about six hours at minus fifteen degrees centigrade. -As stated above, the reaction can be performed in the presence of an excess of the hydrogen halide. It appears, yields are obtained, especially when hydrogen fluoride is employed, when about a molar equivalent of hydrogen halide per mole of steroid oxide (I) is employed. Alternatively, the hydrogen halide can be employed in excess of a molar equivalent and the excess destroyed when the desired oxide opening reaction is substantially complete.

KETONE PROTECTION The ketone protection reaction of the present invention involves the protection of the 3-keto group from reduction 'in the reduction step of the present invention. The 3-keto group is therefore protected by a reduction stable ketonic derivative. selected 3-keto-9whalo-1 1,B-hydroxy-4,17(20)-pregnadiene- '21-oic acid ester (II) is' converted to the corresponding B-ketal (III). The reduction stable ketonic derivatives include the 3-dialkyl ketals, 3-cyclic ketals, 3-hemithioketals, 3-cyclic dithioketals, 3-enol etl1ers, 3-thioenol ethers,

In the illustrative process shown above, the R alkane-ot-diol or alka'ne-fl-diol containing the enamines.

wherein X and R have the values given hereinbefore, Rf and R are each hydrogen or an alkyl group containing less than seven carbon atoms and n is a whole number from one to two, with the R-(CH),,CH--R divalent radical always containing a total of less than nine carbon atoms. Especially preferred are those steroids represented by XIV wherein R and R" are both hydrogen, i.fe.,, the cyclic ketals produced by the reaction of the selected steroid (II) with ethylene glycol, trimethylene glycol, preferably ethylene glycol. 1

Other 3-ketals include the 3-dialkyl ketals, which are somewhat more difficult to prepare in.view of their tendency to be converted to 3-enol ethers. This tendency can be overcome to a certain extent by employing boron trifluoride as the reaction catalyst and less rigorous reaction conditions. The B-hemithiocyclic ketals, e. g, those produced from the reaction of II with m'ercaptoethanol or fl-mercaptopropanol, and the 3-cyclic thioketals, e. g., those produced from the reaction of II with ethylene dimercaptan or propylene dimercaptan are also useful ketone protecting groups.

The enol ethers include the 3-alkyl, 3-alkylthio, 3- .benzyland S-benzylthio enol ethers. These may be represented by Formula III, with an additional double bond int'he 3(4) position, with R representing an alkoxy group,

an alkylmercapto group, an arylalkoxygroup or an arylalkylmercapto group; Preferred among the enol ether groups are the methyl enol ether, the ethyl enol ether, the benz yl ,enol ether, the ethyl thioenol ether, and the benzyl thioenol ether. 1 r

Another reduction stable ketonic derivative which may be employed in the process of the present invention are These compounds may be .represented by Formula III, with an additional double bond at the 3(4) position, with R representing a disubstituted amino radical, e. g., pyrrolidyl, piperidyl, moipholyl, and the dialkylamino radicals, e. g., diallylamino, diethylamino, dimethylamino, etc. Of the enamines, the compounds wherein the disubstituted amino radical is .pyrrolidyl are preferred. The usual operating conditions for the preparation of any of these reduction stable ketonic derivatives involves the reaction of the starting A -3-keto (ll) with the selected alcohol, polyhydric alcohol, mercaptoalcohol, dimercaptan or secondary amine, usually in an inert substantially anhydrous organic diluent. The reaction temperature is usually the refluxing temperature of the selected solvent, e. g., the boiling point of benzene or toluene, and the water of reaction is advantageously removed from the reaction as .it is formed, e. g., as an azeotrope with the selected water-immiscible solvent. Re-

action temperatures from about 25 degrees centigrade to I amines of A -3-keto steroids is claimed in the copending application S. N. 288,546, filed May 17, 1952, of Herr and Heyl, now U. S. Patent 2,781,342.

Amines which may be used in the formation of an enamine ketonic derivative include pyrrolidine, piperidine, C-alkyl substituted pyrrolidines and C-alkyl substituted piperidines, e. g. 2,4-dimethylpyrrolidine, 3-propylpiperidine, 2-methylpyr'rolidine, 3,4-dimethylpyrrolidine, 3- ethylpyrrolidine, 3-isopropylpyrrolidine, 3,3-dimethylpyrrolidine and other lower-alkyl C-substituted pyrrolidines and piperidines. Of these amines pyrrolidine and piperidine are preferred, with pyrrolidine being especially preferred. The selected amine is usually used in a molar excess, calculated on the starting steroid, to achieve the optimum yield of enamine product, The preferred proportion of amine to starting steroid is usually from about 1.1 to about seven moles of amine per mole of steroid and especially from about 1.1 to 2 moles per mole of steroid.

The choice of a particular catalyst in the enamine formation reaction does not appear to be critical since the reaction proceeds in the absence of a catalyst. However, for a substantially complete and rapid reaction, use of a catalyst, preferably a sulfonic acid, e. g., paratoluenesulfonic acid, is preferred.

Moisture in the reaction mixture is detrimental to the procurement of high yields of product and preferred reaction conditions include removal of the water formed during the enamine formation. This is conveniently accomplished by performing the reaction in a water-immiscible solvent and co-distilling the solvent and water as it is formed. Alternatively, the water may be removed by drying agents, e. g., by passing the refluxing solvent, either as the distilling vapor or as the condensate, or both, through a drying agent, e. g., calcium carbide, anhydrous calcium sulfate, anhydrous potassium carbonate, or the like.

Although the reaction may sometimes be performed at room temperature or lower, it is preferably conducted above room temperature, e. g., between about 25 and about 150 degrees centigrade, such temperature conveniently being at or about the boiling point of the reaction mixture.

Reaction times may vary between about a few minutes to several days, depending in part upon the reaction solvent, ratio of' reactants, selected amine, and water removal. When a 3-keto-9ot-halo-llB-hydroxy-4,l7(20)- pregnadiene-2l-oic acid methyl ester and an excess of pyrrolidine are reacted in refluxing benzene accompanied by removal of the water of reaction with para-toluenesulfonic acid being used as catalyst, formation of the S-enamine is substantially complete in less than 1.5 hours.

Reaction solvents which may be employed are preferably the water-immiscible aromatic hydrocarbons and halogenated hydrocarbons, e. g., benzene, toluene, xylene, chlorobenzene, and the like, although other solvents such as, for example, pcntane, hexane, chloroform, methylene chloride, carbon tetrachloride, and the water-miscible solvents, e. g., methanol, ethanol, tertiary butyl alcohol, tetrahydrofuran, dioxane, and other solvents may be used. If a Water-miscible solvent is employed, the removal of the water of reaction is conveniently achieved by the use of a drying agent.

" REDUCTION The reduction step of the process of the present invention, i. e., reduction. of the thus-produced 3-ketone protected 3-keto-9a-halo-l l/i-hydroxy-4, 17 20) -pregnadiene- 2l-oic acid ester, e. g., III, with lithium aluminum hydride or equivalent chemical carboxyl reducing agent in an'organic solvent, e. g., ether, dioxane,tetrahydrofuran, benzene, hexane, mixtures of these and others, preferably ether, preferably followed by decomposition (e. g. hydrolysis) of any excess lithium aluminum hydride or organo-metal complexes, which may be present, converts the 21-oic acid ester group to a 2l-hydroxy group ordinarily without affecting the 3-ketone protecting group. The reaction requires atleast one mole of lithium aluminum hydride for every mole of steriod, but the lithium aluminum hydride is usually employed in substantial excess .of this theoretical amount to ensure optimum yields of desired product. When the steroid and lithium aluminum hydride have been thoroughly mixed, preferably with cooling, the reaction is essentially complete. Continued stirring or heating or both are sometimes employed, however, to ensure completeness of reaction, although heating is usually not necessary and sometimes detrimental. The excess lithium aluminum hydride and any steroid-metal. complex which may be present is prefer'ably decomposed, e. g., by the careful addition of water, an alcohol or carbonyl compound, e. g., ethanol or acetone, to the reaction mixture. If a water-immiscible solvent is employed, the resulting steroid product may be isolated by. adding water and then separating the organic phase from the aqueous phase and then distilling the solvent from the separated layer, or if a water-miscible solvent is employed, by adding sufficient water to precipitate the steriod from the mixture and thereafter separating the steroid therefrom in conventional manner. In either case the steriod product may be recovered by distilling the organic solvent from the reaction mixture.

A preferred procedure comprises reacting the starting 3-ketone protected 3-keto-9a-halo-l lfl-hydroxy-4,l7 (20) pregnadiene-Zl-oic acid ester, e. g., II, with lithium aluminum hydride at a temperature substantially below room temperature, i. e., below twenty degrees centigrade, and then decomposing any excess lithium aluminum hydride and organo-metal complexes thus-formed which may be present with water of organic carbonyl compound. A low reaction temperature ensures a minimum of .side reactions. Water rather than acid is preferred for decomposition of the reaction complex, especially if the 3- ketone protected l1B,21-dihydroxy-4,17(20)-pregnadiene- 3-one, e. g., IV, is to be isolated since this compound is stable under the ensuing conditions when water is used, and the decomposition, using water, is not accompanied by as great a heat of reaction as it is when acid is used for. decomposition of the organo-rnetal complexes which may be present and any excess lithium aluminum hydride. The use of water and low decomposition temperatures is important if the reduction stable ketone protecting group is a 3-enamine since this group is sensitive to heat and acid in aqueous solution. Frequently, the reaction product is somewhat decomposed into non-crystalline non-identifiable products when exposed to acid and heat or the ketone protecting group is somewhat hydrolyzed, thus producing a heterogeneous'reaction product, and the reaction is therefore preferably conducted in the absence of acid.

HYDROLYSIS The hydrolysis step of the process of the present invention involves the removal of the reduction stable ketonic derivative at the 3-position to regenerate the A -3-keto group. This hydrolysis ordinarily involves water, although other ketone regenerating techniques involving removal by interchange reaction with a large excess of acetone or acetaldehyde, in the presence of, for example, para-toluenesulfonic acid, may be employed.

If water is the hydrolyzing or ketone regenerating agent, the conditions necessary to achieve satisfactory hydrolysis depend somewhat upon the reduction stable ketonic derivative employed. For example, if a ketal or enol ether is the protecting group, the hydrolysis ordinarily requires acidic aqueous conditions. A 3-enamine, however, is susceptible to alkaline hydrolysis. Since the mixture resulting from an aqueous decomposition of any organo-metal complexes and excess lithium aluminum hydride remaining after the reduction step is alkaline, when the ketone protecting group is an enamine, prolonged contact with the thus-produced 3-amino-9ot-halol15,21-dihydroxy-2,4,l7(20)-pregnatriene with the total reaction mixture may result in the hydrolysis 'ofthe grees centigrade.

and separation of 9 3-amino group, thus-producing a 9dhalO-1lfi,21-dlhydroxy-4,l7(20)-pregnadiene-3Fone (V). In this case, the reduction step and the hydrolysis of the present invention become substantially one step since they are performed concurrently, or at least by a continuous reaction.

Although, in the hydrolysis of a 3-enamine to regenerate the A -3keto group, either organic or mineral acids may be used, mineral acids do not appear to give as clear cut a reaction as organic acids, for example, buffered acetic acid. Bases are preferred over acids for the hydroylsis of the enamine group since the hydrolysis reaction is usually a faster, cleaner reaction under alkaline conditions. Even neutral conditions may be employed if the reaction time is of sufficient duration or the reaction temperature is sufliciently high. For example, the 3- enamine group can be converted to a A -3-keto group by heating the selected S-enamine steroid for about eighteen hours in refluxing 95 percent methanol. If a small amount of base is added, e. g., sodium hydroxide, potassium carbonate, sodium bicarbonate, or the like, the reaction is usually complete in less than anhour at aboutthirty de- Acidification of the resulting mixture the organic layer, if Water-immiscible, or extraction of the resulting solution with methylene chloride, benzene or the like, if water-miscible, and then distillingthe solvent therefrom, separates the thus-produced 9ot-halo-l lfl,21-dihydroxy4,17(20)-pregnadiene-3 one (V). p I

The hydrolysis of a 3-dialkyl ketal, cyclic ketal, enol ether, thioenol ether, hemithioketal, or dithioketal to regenerate a A -3-keto group, inthis instance to produce 90: halo Ill-3,21 dihydroxy -4,l7(20) pregnadiene- 3-one, can be'performed according to the well known reaction conditions known in the art. The hydrolysis is ordinarily an acidic one, since these protecting groups are quite stable to base. The more rigorous reactionconditions should be avoided however, to prevent undue alteration of the steroidal structure at other parts of the mole- .cule, e. g., at carbon atomll, 17 or 21.

ESTERIFICATION The esterification step of the process of the present i11- vention involves the conversionof the 2l-hydroxy group of 90t-ha10-1 1B,21.-dihydroxy-4,17 (20) -pregnadiene-3-one (V) to a 21-ester group (VI). This can be performed under the esterification conditions known in the art, e. g., by the reaction of V with the selected acid anhydride'or acid chloride, preferably in the presence of pyridine or other N-cycloaromatic tertiary amine; with the free. acid, e. g., formic acid or other weaker acid in the presence of an esterification catalyst, e. g., para-toluenesulfonic acid or sulfuric acid; with an ester by ester interchange reaction; or by reaction with the ketene of the selected acid.

Since the llfi-hydroxy group is relatively labile, reaction conditions which are not apt to cause dehydration, or alteration in some other manner, of the llfl-hydroxy group are preferred. The preferred esterification reagent is acetic anhydride, preferably in the presence of pyridine, producing a compound represented by Formula VI wherein R' is acetyl.

OXIDATIVE HYDROXYLATION The oxidative hydroxylation stepof the present invention consists of the concomitant reaction of a 9u-halo- 11o: hydroxy 21 acyloxy 4,17(20) pregnadiene 3- one (VI) with a hydroxylating agent and an oxidizing agent to produce a 9a-halo1 1,6,17a-dihydroxy 2l-acyloxy- 4-pregnene-3,20-dione (VII). i

The hydroxylation of a A -21-'acyloxy steroid to produce a 17e,20-dihydroxy steroid is a well known reaction. See, for example, Ruzicka and Acta 22, 57 (1939), and U. S. Patent 2,492,194. In this reaction, a metal oxide is ordinarily employed to add to the double bond to produce, upon hydrolysis, a glycol. Osmium tetroxide is ordinarily the metal oxide. of choice.

Mueller, Helv.Chim.

ethanol oxide peroxide, etc.

For a discussion of the hydroxylating abilitiesof the metal oxides, preferably from sub-groups IV, V and VI of the periodic table, see Milas, J. Am. Chem. Soc. 59, 2342 (1937), and Mugden and Young, J. Chem. Soc. 1944, 2988. Examples of other hydroxylating metal oxides or derivatives thereof include osmium tetroxide, manganese dioxide, tungstic acid, permolybdic acid, selenium dioxide, etc.

The first recognized example of an oxidative hydroxylation of a steriod is found in Prins and Reichstein, Helv. Chim. Acta 25, 300 (1942). There is reported, using osmium tetroxide and chloric acid, the oxidative vhydroxylation of a A steroid to produce a 20-keto-21- hydroxy steroid. The concept of oxidative hydroxylation outside the field of steroidal chemistry was first demon strated, employing a catalytic amount of osmium tetroxide with hydrogen peroxide, by Crigee, Annallen der Chemie 522, 75 (1936). I

Oxidizing agents which may be employed in the oxidative hydroxylation step of the present invention are the oxidizing agents which contribute an oxygen atom to the reaction and include, hydrogen peroxide, alkyl peroxides, peracids, chloric acid, periodic acid, acetyl peroxide, benzoyl peroxide, tertiary amine oxide peroxides, aryliodo oxides, lead tetraacetate, manganese dioxide, mercury diacetate, etc., i. e., oxygen donating oxidizing agents. The use of osmium tetroxide and hydrogen peroxide in the oxidative hydroxylation of certain A -ZI-Substituted steroids is claimed in U. S. Patents 2,662,854 and 2,668,- 816. The use of amine oxide peroxides: with. osmium tetroxide in the oxidative hydroxylation of A -21- acyloxy steroids is claimed in the copending application of Schneider and Hanze, S. N. 424,315, now U. S. Patent 2,769,823, and the use of aryliodo oxides with osmium tetroxide in the oxidative hydroxylation of these same steroids is claimed in the copending application of Schneider, S. N. 443,418. The use of an amine oxide peroxide or an aryliodo oxide as the oxidizing agent in the oxidative hydroxylation of the present invention is preferred. The use of these reagents is discussed more fully below. I r

The amine oxide peroxides which may be employed in the oxidative hydroxylation step of this invention are prepared by the reaction of some tertiary amines with two molar equivalents of hydrogen peroxide or by the reaction of a tertiary amine oxide with one molar equivalent of hydrogen peroxide. Amine oxide'peroxides are a novel class of oxidizing agents. For the most part, they have a higher oxidation potential than the hydrogen peroxide from which they were prepared.

The amine oxide preferably non-aromatic, i. e., the molecule is devoid of an aromatic group of any kind. The non-aromatic tertiary amine oxide peroxides include the N-alkylcycloalkylamines oxide peroxides, e. g., N-alkylmorpholine oxide peroxide, N-alkylpyrrolidine oxide peroxides, and N-alkylpiperidine oxide peroxides, the trialkylamine oxide peroxides, e. g., trimethylarnine oxide peroxide, triethyl amine oxide peroxide, methyldiethylamine oxide peroxide, ethyldirnethylamine oxide peroxide, the alkanolamine oxide peroxides, e. g., dimethylethanolainine oxide peroxide, pyrrolidylethanol Of these amine oxide peroxides, triethylamine oxide peroxide and N-methylmorpholine oxide peroxide are especially advantageous.

The organic polyvalent iodo oxides which maybe em- I ployed in the oxidative hydroxylation step of thisinvention are organic iodo compounds having at least one titratable oxygen atom attached to the iodine atoms. The presence of a titratable iodo oxide oxygen atom can be determined in the usual manner with KI, acid and sodium thiosulfate. The known examples of these iodo oxides are iodoso,

vanadium pentoxide, chromium trioxide, perperoxides of the present invention are oxide peroxide, pipcridyliodyl and iodoxy compoundsand salts I I i thereof. The iodonium compounds are not included in 3 the term iodo oxides as used herein since thehydroxy wertigen Jod," F. Enke, Stuttgart (1914).

group of the iodonium compounds is ionic in nature and is not therefore directly attached to the iodine atom, but merely associated with it ionically. The iodoso compounds-have one oxygen atom attached to the iodine atom; the iodoxy compounds have two oxygen atoms attached.

1 Any excellent reference to these iodo oxides is Willgerodt, Die Organischem Verbindungen Mit Mehr- Many iodo oxides are disclosed in this reference. Other references include R. Sandin, Organic'Compounds of Polyvalent Iodine, Chem. Rev. 32, 249 (1943); Sidgwick, Chemical Elements and Their Compounds, vol. II, 1243-1260, Oxford Univ. Press (1950); and Mason et al., J. Chem. Soc. 1935, 1669. The latter reference discloses the iodyl compounds.

From these references, it appears that iodo oxides can be prepared from aryl iodo compounds or other vinyl iodides whose double bond is also modified in some way, e. g.,by halogenation, as in a-chloro-iodoethylene, chloro iodofumaric acid or a-chloro-iodoacrylic acid.

Examples of the known aryl iodo oxides include iodosobenzene, phenyliodosoacetate, diphenyliodyl hydroxide and acetate, phenyliodosopropionate, iodoxybenzene, the ring alkylated iodoso and iodoxybenzenes, and the oxides of iodonaphthylene, iodobenzoquinone and iodoanthroquinone, iodobenzoic acid, iodobenzenesulfonie acid, iodobenzaldehyde, iodobenzophenone, iodosalicylic acid, etc. The heterocyclic aryl iodo oxides, e. g., of the pyridine, thiophene and furan series, do not appear to be known, but are included in the term aryl iodo oxide.

The preferred organic polyvalent iodo oxides employed in the process of the present invention are the carbocyclic aryl iodo oxides. Of these the aryl iodoso compounds are preferred, e. g., iodosobenzene and phenyliodosoacetate, which have been found to give especially good results. The iodoxy compounds, for the most part, are very insoluble in organic solvents, and therefore do not usually give as satisfactory results as the corresponding iodoso compounds with respect to reaction rate and/or yield of l7-hydroxy-20-keto product.

The preferred aryl iodoso compounds are ordinarily prepared by the reaction of any aryl iododichloride with a base, e. g., sodium hydroxide. The aryl iodoso acid salts can be prepared by the reaction of an aryl iodide with the selected organic peracid. The iodoxy compounds are prepared by boiling the corresponding iodoso compounds in water or by oxidizing an aryl iodide with, for example, Caros acid. The iodyl hydroxides are prepared by the reaction of an aryl iodoxy compound with two molar equivalents of sodium hydroxide in a one normal aqueous solution of sodium hydroxide at zero degrees centigrade for about 1.5 hours. See Mason (loc. cit.). The salts of aryl iodyl hydroxy' compounds are prepared by precipitating the aryl iodyl hydroxide as the carbonate and reacting the carbonate with the selected acid.

In carrying out the oxidative hydroxylation step of the invention, the starting steroid is advantageously dissolved in an inert organic solvent, for example, tertiary butyl alcohol, diethyl ether, tetrahydrofuran, or the like, and the hydroxylating agent preferably osmium tetroxide and the oxidizing agent mixed therein. Advantageously, though not necessarily, the hydroxylating agent is added after the addition of the oxidizing agent. Advantageously also, the osmium tetroxide and the oxidizing agent peroxide are added in solutions of the same solvent used as the vehicle used for the reaction.

. The amount of the preferred osmium tetroxide hydroxylating agent employed in the reaction can be varied widely, for example, from about 0.2 molar equivalent to 0.001 molar equivalent. Advantageously, however, not more than 0.05 molar equivalent is used.

1 The amount of oxidizing agent theoretically required to produce a l7-hydroxy-20-keto-21-acyloxy steroid is two oxidizing equivalents for each mole of osmate ester formed in the reaction. It has been found, however, that in the process of this invention, more than the theoretical amount of oxidizing agent is ordinarily necessary to obtain a complete reaction. For optimum results in the process of this invention, therefore, it is usually necessary to'use the oxidizing agent in excess of the theoretical amount. For example, optimum results are ordinarily obtained using between about 2.2 and about 2.75 equivalents of amine oxide peroxide or aryl iodo oxide, calculated on the starting steroid. The course of the oxidative hydroxylation reaction can be readily determined by the titration of aliquot portions for residual oxidizing agent. Ordinarily, the presence of small amounts of water in the reaction mixture does not adversely affect the yield of desired product. However, to ensure optimum yields of desired product when employing hydrogen peroxide or an amine oxide peroxide, the reaction advantageously may be performed under substantially anhydrous conditions, e. g., in dry tertiary butyl alcohol, or like solvent.

The reaction temperature for the oxidative hydroxylation step normally is between about fifteen and about thirty degrees centigrade although higher or lower temperatures are operable, e. g., between about minus ten' PREPARATION 1 Methyl 3-ket0-11 a-hydr0xy-4,1 7(20) -pregnadiene-21 -0ate To a stirred solution of 22.60 grams (0.05 mole) of the sodium enolate of 11a-hydroxy-21-ethoxyoxalylprogesterone (U. S. 2,683 ,724) in 550 milliliters of methanol was added dropwise sixteen grams (0.1 mole) of bromine. To the thus-produced solution of 29.4 grams (0.05 mole) of 11whydroXy-Z1,21-dibromo-2l-ethoxyoxalylprogesterone in 550 milliliters of methanol was added a solution of 16.5 grams (0.3 mole) of sodium methoxide in 500 milliliters of methanol. The reaction mixture was maintained at about 25 degrees centigrade for sixteen hours where after an equal volume of water was added thereto and the whole was extracted with about equal portions of first benzene and then two portions of methylene chloride. The combined extracts were dried with anhydrous sodium sulfate and thereafter distilled to remove the solvent therefrom. The distillation residue was dissolved in 500 milliliters of methylene chloride and chromatographed over 875 grams of Florisil synthetic magnesium silicate. The column was developed with 1,250-milliliter portions of solvents of the following composition and order: four of methylene chloride plus five percent acetone, four of methylene chloride plus ten percent acetone, four of methylene chloride plus fifteen percent acetone, two of methylene chloride plus twenty percent acetone, and finally, two of acetone. The methylene chloride plus ten percent acetone eluates and the first methylene chloride plus fifteen percent acetone eluate were combined and the solvent distilled therefrom. The seven grams of distillation residue was recrystallized from a mixture of ethyl acetate and Skellysolve B hexane hydrocarbons'to yield crystalline methyl 3-keto-1la-hydroxy-4,17(20)-pregnadiene-21-oate, melting at 205 to 210 degrees centigrade.

Analysis.-Calculated for C H O C, 73.75; H, 8.48. Found: C, 73.77, 74.10; H, 8.38, 8.59.

Similarly, other 3-keto-l 1a-hydroxy-4, 17 (20) pregnadiene ZI-oic acid esters are prepared wherein the ester is methyl, propyl, butyl, amyl, hexyl, heptyl, octyl, or the like, by replacing the sodium methoxide in methanol 13 used in the above-described reaction by the selected alkalimetal alkoxide in an alkanol.

PREPARATION 2 M ethyl 376210-110 (partr'toluenesulfonyloxy) 4,17 (20 -pregnadiene-21 oate .residue was dissolved in 25 milliliters of chloroform and poured over a chromatographiccolumn of 75 grains of Florisil synthetic magnesium silicate. The column was developed with 100 milliliter portions of solvents of the following composition and order: three of Skellysolve B hexane hydrocarbons plus five percent acetone, three of Skellysolve B plus ten percent acetone, three of Skellysolve B plus twenty percent acetone, three of Skellysolve B plus thirty percent acetone and two of acetone. The Skellysolve B plus thirty percent acetone eluted 1,262 grams, a yield of 88.5 percent of the theoretical, of methyl 3-keto-11a-(para-toluenesulfonyloxy)- 4,17(20)-pregnadiene-2l-oate which, after crystallization from a mixture of 25 milliliters of hot acetone and 75 milliliters of Skellysolve B, weighed 1.03 grams, melted at 149 to 153 degrees centigrade, had an optical rotation, [d of plus seventy degrees in acetone and the analysis below.

Calculated for C H O S: C, 67.96; H, 7.08; S, 6.25.

- Found: C, 68.08; H, 7.54; S, 6.25.

Similarly, other 3-keto-11ot-(para-toluenesulfonyloxy)- 4,17(20)-pregnadiene-21-oic acid esters are prepared by substituting other esters of 3-keto-11ct-hydroxy-4,17(20)- pregnadiene-Zl-oic acid in the esterification reaction with para-toluenesulfonyl chloride, e. g., alkyl esters and preferably lower-alkyl esters, for example, the ethyl, propyl, butyl, amyl, hexyl, heptyl, or octyl ester.

Following the procedure described in Preparation 2, but substituting another esterifying agent which produces an lla-sulfonyloxy ester, other methyl 3-keto- 11w- (sulfonyloxy)- 4,17(20)- pregnadiene- 21- oates are prepared. Examples include those wherein the sulfonyloxy group is m-toluenesulfonyloxy, benzenesulfonyloxy, para-biphenylsulfonyloxy, para-methoxybenzenesulfonyloxy, 2,6-dimethylbenzenesulfonyloxy, or the sul-fonyloxy groups produced by the reaction of methyl 3- reto-lluhydroxy-4,17(20)-pregnfidiene-21-oate with an arylsulfonyl chloride shown in Tables II, IV, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI and XVII (pages 463 to 496) of Suter, Organic Chemistry of Sulfur, Wiley pub. (1944), which preferably contain but one acid chloride group, to produce the corresponding ester thereof. Substituting another lower-alkyl ester of3- keto-l1u-hydroxy-4,17(20)-pregnadiene-21-oic acid for the corresponding methyl ester in these reactions will produce the corresponding lower-alkyl 3-keto-11a-(sulfonyloxy 4, 17 20) -pregnadiene-2 1 -oate.

, PREPARATION 3 M ethyl 3-ket0-4,9(11 ),17(20)-pregnatriene-21-0ale A solution of 500 milligrams of methyl 3-keto-11a- (para-toluenesulfonyloxy) 4, 17 20 pregnadiene-Z l-oate in ten milliliters of collidine was refluxed at 172 degrees centigrade for thirty minutes. The reaction mixture wasthen cooled to room temperature and mixed with 100 milliliters of diethyl ether. The collidine was removed from the ether by washing with cold five percent hydrochloric acid. The ether layer was then dried over anhydrous sodium sulfate, filtered and the ether then distilled. There was thus obtained 0.316 gram of methyl 3-keto-4,9(11),17(20)-pregnatriene-21-oate which, after crystallization from a mixture of acetone: and Skellysolve B, weighed 0.31 gram, a yield of 93.5 percent of the theoretical, melted at to degrees centigrade and had the analysis below.

Calculated for 0 mm,: C, 77.61; H, 8.28. Found: C, 77.58; H, 8.19.

Following the procedure described in. Preparation 3, methyl 3-keto-4,9(1l),17(20)-pregnatriene-21-oate can be prepared by the reaction of methyl 3-keto-11e-(paratoluenesulfonyloxy)-4,17(20) -pregnadiene-21-oate with sodium acetate in boiling glacial acetic acid, refluxing methanol or absolute ethanol, five percent ethanolic potassium hydroxide, or potassium acetate in boiling aqueous acetone, sodium formate in refluxing methanol, or similar reagent.

Similarly, substituting another lloc-StllfOHYlOXY ester of methyl 3-keto-1la-hydroxyt,17(20)-pregnadiene-21- oate, for example, the esters disclosed in the paragraphs following Preparation 2, in the reaction described in Preparation 3, there is also produced methyl 3-keto- 4,9( l1),17(20)-pregnatriene-2loate.

Other esters ,of I 3-keto-4,9 1'1),17 (20)-pregnatriene-21- oic acid wherein the ester group is, for example, aralkyl, alkaryl, or preferably lower-alkyl, e. g., ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, are prepared by substituting the corresponding ester of 3-lreto-1la-(paratoluenesulfonyloxy)- 4,l7(20)- pregnadiene-21- oic acid or other lldr-S'LllfOIlYIOXY ester of an alkyl 3-keto-11w hydroxy-4,17(20)-pregnadiene-21-oate in the reaction de scribed in Preparation 3 or the paragraph following.

EXAMPLE 1 Methyl 3 ket0-9u-brom0-11B-hydroxy-4J7(20)-pregnadiene-ZI-oate methylene chloride thendistilled at reduced pressure. The

residue was dissolved in benzene and poured, over a chromatographic column .of grams of Florisil synthetic magnesium silicate. The column was developed with300 milliliter portions of solvents of the following composition and order: nine of Skellysolve B hexane hydrocarbons plus five percent acetone, seven of Skellysolve B plus 7.5 percent acetone,five of Skellysolve B plus ten percent acetone and one of acetone. The Skellysolve B plus 7.5 percent acetone eluates contained the methyl 3-keto- 90c bromo 11,6-hydroxy-4,17(20)-pregnadiene-21-oate which, after crystallization from a mixture of acetone and Skellysolve B, weighed 2.53 "grams, a yield of 58 percent-ofthe theoretical, and melted at 105 to 108 degrees centigrade. Recrystallization of this product from the same solvent mixture raised the melting point to 108 to 109 degrees centigrade (decomposition). Infrared spectrum analysis was consistent with the structure.

Following the procedure described in Preparation 4, other esters of 3-keto-9u-bromo-l1fi-hydroxy-4,17(20)- pregnadiene-Zl-oic acid, e. g., lower-alkyl esters, ethyl, propyl, butyl, amyl, .hexyl, heptyl, octyl, are prepared by substituting the corresponding ester of 3-keto-4,9(11), 17(20)-pregnatriene-21-oic acid in the reaction described in Example 1. t

Methyl 3 keto-9a-iodo-11,B-hydroxy-4,l7(20)pregnaiodide.

EXAMPLE 2 Methyl 3 ket-9:11-[3-ep0xy-4,17(20)-pregnadiene-21- oate A mixture of 2.53 grams (5.78 millimoles) of methyl 3 keto 9a-bromo-11B-hydroxy-4,17(20)-pregnadiene- 21-0ate, three grams of anhydrous potassium acetate and 100 milliliters of absolute methanol was heated at the refluxing temperature of the mixture for 2.5 hours. The cooled solution was then diluted with two volumes of water and extracted thoroughly with methylene chloride. The methylene chloride extract was dried and then the solvent evaporated therefrom at reduced pressure. The residue was dissolved in benzene and then poured over a chromatographic column of 100 grams of Florisil synethetic magnesium silicate. The column was developed with 200 milliliter portions of solvents of the following composition and order: nine of Skellysolve B plus five percent acetone, five of Skellysolve B plus 7.5 percent acetone, five of Skellysolve B plus ten percent acetone, and one of acetone. The Skellysolve B plus five percent acetone eluates contained 1.24 grams, a yield of sixty percent of the theoretical, of methyl 3-keto-921l- B-epoxy-4,l7(20)-pregnadiene-21-oate which, after crystallization from Skellysolve B containing a trace of acetone, yielded heavy needles melting at 123.5 to 125 degrees centigrade and having an optical rotation [uIl in chloroform of plus 48 degrees and the analysis below.

Calculated for C H O C, 74.13; H, 7.92. Found: C, 74.33; H, 7.83.

Substituting another ester of 3-keto-9u-brorno-11B-hydroxy-4,17(20)-pregnadiene-21-oic acid, e. g., ethyl, propyl, butyl, amyl, hexyhheptyl, octyl, or other loweralkyl ester, in the reaction described above is productive of the corresponding ester of 3-keto-9:l1-B-oxido-4,17 (20)-pregnadiene-2l-oic acid.

EXAMPLE 3 A solution of four grams (1.12 millimoles) of methyl 3 keto 9:11-B-oxido-4,17(20)-pregnadiene-21-oate in fifty milliliters of alcohol-free chloroform was cooled to zero degrees centigrade. To the cooled solution was added 25 milliliters of an ice cold solution of anhydrous hydrogen fluoride in alcohol-free chloroform containing about one gram of hydrogen fluoride whereupon a red color developed. The solution was stored at minus fifteen degrees centigrade for four hours with occasional stirring. The solution was then washed with aqueous sodium bicarbonate and then with water. The washed chloroform solution was dried and then distilled to drymess. The partially crystalline residue was dissolved in benzene and poured over a column of 20.0 grams of Florisil synthetic magnesium silicate. The column was developed wtih 200 milliliter portions of solvents of the following composition and order: ten of Skellysolve B plus five percent acetone, five of Skellysolve B plus 7.5 percent acetone, five of Skellysolve B plus ten percent acetone, and one of acetone. The Skellysolve B plus 7.5 percent acetone eluates contained the methyl 3-keto- 9a fluoro 1lB-hydroxy-4,17(20)-pregnadiene-21-oate which, after crystallization from a mixture of acetone and Skellysolve B, melted at 245 to 247 degrees centigrade, had an infrared spectrum absorption consistent with the structure and the analysis below. The Skellysolve B plus five percent acetone eluates contained 1.40 grams of starting steroid.

Calculated for C H FO C, 70.19; H, 7.76; F, 5.05. Found: C, 70.28; H, 7.71; F,'4.86.

Following the procedure described in Example 3, ethyl 3-keto-9:l1-[3-oxido-4,17(20)-pregnadiene-21-oate is similarly converted to ethyl 3keto-9a-fluoro-11B-hydroxy-4, 17(20)-pregnadiene-2l-oate. Other esters of 3-keto- 9:l1-,B-oxido-4,17(20)-pregnadiene-2l-oic acid are similarly converted to the corresponding esters of 3-keto-9ufiuoro 115 hydroxy 4,17(20) pregnadiene 21 oic acid. Preferred esters of 3-keto-9:ll-fi-oxido-4,17(20)- pregnadiene-Zl-oic acid are those substantially unaffected by the hydrofluoric acid, e. g., hydrocarbon esters, especially saturated hydrocarbon esters, and particularly alkyl esters, preferably containing from one to eight carbon atoms, inclusive, e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, amyl, hexyl, heptyl, and octyl esters of 3-keto-9:11-[3-oxido-4,l7(20)-pregnadiene: 2l-oic acid which are converted to the corresponding esters of 3keto-9a-fluoro-l1[3-hydroxy-4,17(20)-pregnadiene-Zl-oic acid.

EXAMPLE 4 Methyl 3-keto-9a-chlor0 11e-hydroxy4,17(20)- pregnadiene-Z] -0ate Following the procedure described in Example 3, but

substituting hydrogen chloride for the hydrogen fluoride,

alkyl esters of 3-keto-9m-chloro-1lB-hydroxy-4,l7(20)- pregnadiene-Zl-oic acid.

EXAMPLE 5 The 3-ethylene glycol ketal of methyl 3-ket0-9uuoro- 11fl-hydr0xy-4,17(20)-pregnadiene-21-0ate A mixture of 430 milligrams (1.4 millimoles) of methyl 3 keto c fluoro 11B hydroxy 4,17(20)- pregnadiene-Zl-oate, three milliliters of ethylene glycol, milligrams of para-toluenesulfonic acid monohydrate and fifty milliliters of anhydrous benzene was heated at the refluxing temperature of the mixture for six hours with concomitant and continuous removal of the water of reaction with a Dean-Stark water trap. The mixture was then cooled, washed with aqueous sodium bicarbonate and then with water, and distilled at reduced pressure to dryness. The crude crystalline residue consisted essentially of the 3-ethylene glycol ketal of methyl 3-keto- 9a-fll101'0-1 lfl-hydroxy-4,17(20)-pregnadiene-21-oate.

Following the procedure described in Example 5, other 3-ketals of methyl 3-keto-9a-fluoro-llit-hydroxy- 4,17(20)-pregnadiene-21-oate are prepared by the reaction of methyl 3-keto-9a-fluoro-11fi-hydroxy-4,17(20)- pregnadiene-Zl-oate with the selected alkane-a-diol or alkane-B-diol, e. g., lower-alkane-aand fi-diols, propylene glycol, trimethylene glycol, butane-2,3-diol, pentane- 1,2-dicl, pentane-2,4-diol, hexane-1,3-diol, heptane-1,2- diol, octane-1,2-diol, etc.

Similarly, substituting other esters of 3-keto-9a-fluorol.le-hydroxy-4,17(20)-pregnadiene-2l-oic acid as the starting steroid in the reaction described in Example 5 is productive of the 3-ethylene glycol ketal of these esters of 3-ket0-9ot-fluoro-1 15-hydroxy-4,l7(20)-pregnadiene-21- oic acid, e. g., the S-ethylene glycol ketal of alkyl 3-keto- 90a fiuoro 11 8 hydroxy 4,17(20) pregnadiene 21- oates wherein the alkyl group is ethyl, propyl, isopropyl, isobutyl, sec-butyl, amyl, hexyl, heptyl, octyl, etc. Substituting other alcohols and glycols in the reaction, e. g.,

the alkane-a-diols and alkanerfi-diols named above, is productive of the corresponding 3,-ketal' of the starting alkyl 3-ket0-9wfiuoro-1 lfi-hydroxy-4, 17 20) -pregnadiene 21-oate.

EXAMPLE 6 The 3-etlzylene glycol ketrzl methyl 3-ket0-9a-chloro- 1 Zfl-hydroxy-4,1 7 2 0 -pregna zl lane-21 -oate Following the procedure described in Example 5, but substituting methyl 3-keto-9a-chloro-11B-hydroxy-4,l7- (20)-pregnadiene-2l-oate for the methyl 3-keto-9a-fluoro- 11fl-hydr0Xy-4,17(20)-pregnadiene-2l-oate, there is thusproduced the 3-ethylene glycol ketal of methyl 3-keto-9achloro-1 lfl-hydroxy-4,17(20)-pregnadiene-2l-oate.

Similarly, substituting other alkane-a-diols or alkanefl-diols, e. g., lower-alkane-aand l8-diols, propylene glycol, trimethylene glycol, butane-2,3-diol, pentane-1,2- diol, pentane2',4-diol, hexane-1,3diol, heptane-LZ-diol, octane-1,2-diol, as the ketalizing agentin the reaction described above, the corresponding 3-cyclic ketals of methyl 3 L keto 90c chloro 11,8 hydroxy 4,17(20)- pregnadiene-Zl-oate are prepared.

Substituting other esters of 3-keto-9ot-chlor0-11B-hy droxyl,l7 (20) pregnadiene-2l-oi'c acid in this reaction isproductive of the ketal produced by the reaction of the selected alkane-wdiol or alkane-fl-diol and the selected ester of 3-ket o-9a-chloro-ll,8-hydr0xy-4,17(20)-pregnadiene-Zl-oic acid. g

EXAMPLE 7 Methyl 3-pyrrolidyl-9ot-flu0ro-1 Jfl-h ydroxy-3,5,1 7(20) pregnatrien-ZI -oale Methyl 3-pyrrolidyl-9a-fluoro-1 1B-hydroxy-3,5,17(20) pregnatriene-Zl-oate is prepared by the reaction of methyl 3 keto 9a fluoro 1 1 8 hydroxy 4,17(20) pregnadiene-Zl-oate with pyrrolidine in benzene, at the refluxing. temperature of the mixture at slightly reduced pressure, in the presence of a reaction catalyst of paratoluenesulfonic acid. The water of reaction is continuously removed with a watertrap.

Substituting other alkyl esters of 3-keto-9a-fiu0ro-ll/3- hydroxy-4,17(20)-pregnadiene- 2l-oic acid as starting material for the enamine reaction is productive of the corresponding, alkyl 3-pyrrolidyl-9a-flunro-llflhydroxy- 3,5,17('20,)-pregnatriene-2lroate. Substituting another active secondary amine as reactant, preferably 'a cyclic aminege; g., alkylpyrrolidines, Z-methylpyrrolidine, piperidine alykylpiperidines, B-methylpiperidine, morpholine, etc., ,is productive of the corresponding alkyl 3- amino- 9oz lluoro 11,8 hydroxy -3,5,17(20) pregnatriene-ZI-Oate.

Substituting the corresponding alkyl 9a-chloro-l1/3-hydroxy-4,11(20)pregnadiene-2 l-oate in any of the enamine reactionsdescribed above, is productive of the corresponding alkyl 3,5,17(20)-pregnatriene-21roate, e. g., methyl 3-pyr rolidyl 19 chloro,-, 11 3 hydroxy 3,5,l7(20)' preg- EXAMPLE 8 k Reacting methyl 3 keto 9a fiuoro 11B hydroxy- 4,l7(20)-pregnadiene 2l-oate With ethyl alcohol in the presence of boron trifiuoride at the refluxing temperature of the ethyl alcohol is productive of methyl 3- ethoxy 9a fiuoro-llfl hydroxy-3,5,l7(20)-pregnatri- 4,17(20), p17egnadiene 21-oate and these agents are prepared. Substituting other alkyl esters 3-amino-9a-chloro-11,8-hydroxyfluoro 11,8 hydroxy 4,1'7(20) pregnadiene 21 oic acid, e. g., ethyl, propyl, isopropyl, butyl, amyl, isoamyl, hexyl, heptyl, octyl, etc., for the methyl ester shown above is productive of the corresponding 3-enol etherified alkyl ester of 3-keto-9a-fiuoro-1lfl-hydroxy-4,17(20)- pregnadiene-2l-oate.

Substituting the corresponding 9a-chloro compound for one of the 9a-fiuoro compounds named above, e. g., methyl 3-k6i0 9cc-ChlOIO-1 1/3-hydr0xy 4, 17 (20) -pregnadiene-ZI-oate, as starting steroid, results in the production of a '3-enol ether of these 9ot-chloro'compounds, e.g., methyl 3 ethoxy 9oz. chloro 11,8 hydroxy 3,5, 17 (20 -pregnatriene-2 l-oate. l

EXAMPLE 9' The S-ethylene glycol ketal of 9a-flu0r0-I 1,8,2] -dihydroxy- 4,17(20)-12regnadiene-3-0ne 1 l The crude crystalline ketal obtained as.v the reaction product of a ketalization conducted in exactly the man ner described in Example 5 was dissolved in 25 milli liters of benzene and then added dropwise to a stirred suspension 050.5 gram oflithium aluminum hydride and fifty milliliters of ether. After the addition of the henzene solution was completed, the stirring was continued for 1.5 hours. The excess lithiurn aluminum hydride in the reaction mixture Was then decomposed by the drop- Wise addition offive milliliters of ethyl acetate. Ten milliliters of water was then slowly added to the mixture followed by 25 milliliters of solution of five milliliters of concentrated hydrochloric acid and twenty milliliters of water. The benzene layer was separated and washed with an aqueous solution'of sodium bicarbonate followed by water. The benzene solution was then dried and distilled to dryness toleave a distillation residue consisting essentially of the 3-ethyle ne glycol ke'talof 9a-fiuoro- 1-1 ,6,21-dihydroXy-4, 17 20 )-pregnadien e-3-one.

Following the procedure described in Example 9, other i 3-cyclic ketals of 9a-fluoro-11;8,21-dihydroxy-4,,17(20)- pregnadiene-B-one are prepared by the lithiumalurninum hydride reduction of the corresponding 3-cyclic ketal of an ester of 3-keto-9ot-fiuoro-1lfl-hydroxyw t,17(20')-preg nadiene-Zl-oate, e. g., the 3-propylene glycol ketal, 3- trimethylene glycolketal, 3butane-l,2-diol ketal, 3-peritane-l,2diol ketal, 3-pentane-2,4 diol ketal, hexane-1,3,- diol ketal, heptane-1,2-diol ketal, octane-1,2-diolketal of, for example, the methyl ester of 3-keto-9vr-fiuoro-11;3- hydroxy-4,17(20)-pregnadiene-21-oic acid, or other alkyl ester, e. g., ethyl, propyl, isopropyl, isobutyl, sec-bu'tyl, amyl, hexyl, heptyl, octyl, etc.

EXAMPLE 10 Following the procedure described in Example 9, but

one. 1

Substituting other 3-cyclic ketals of methyl skew-9&- chloro 11,8 hydroxy 4,17(20), pregnadiene 21- oate, wherein the 3-cyclic ketal is, e. g.,,the propylene glycol, trimethylene glycol, butane- 2,3-didl, pentane-l,2- diol, pentane-2,4-diol, hexane-1,3-diol, heptane-1,2 -diol, or octane-l,2-diol ketah'as starting steroid in the reac tion described in Example 9 is productiveof thecorrespending Z-cyclic ketal of 9a chloro-11fl,21-dil1ydroxy- 4,17(20)-pregnadiene-3-one.

EXAMPLE 11 pregnatriene Following the procedure described in Example 9, but

asraaoo 9oz fluoro 11,3 hydroxy 3,5,l7(20) pregnatriene- 2l-oic acid, as starting steroid in the reduction is productive of the corresponding 3-enamine of 9ot-fil10lO-1l,6,21- dihydroxy-4,17(20)-pregnadiene-3-one.

Substituting the corresponding 9e-chloro compound for one of the 9a-fluoro enamines described in Example 11 is productive of the corresponding 3-enamine of 9achloro 11fl,21 dihydroxy 4,17(20) pregnadiene 3- one, e. g., 3-pyrrolidy1-9u-chloro-11fl,21-dihydroxy-3,5, 17 (20)-pregnatriene from methyl 3-pyrrolidyl-9a-chloro- 1,1 fl-hydroxy-3 ,5 17 (20) -pregnatriene-21-oate.

V EXAMPLE 12 3 e'thoxy 9a fluoro 115,21 dihydroxy 3,5,17(20)- pregnatriene Following the procedure described in Example 9, but substituting methyl 3 ethoxy 9a fluoro 11,8 hydroxy- 3,5,17(20)-pregnatriene-2l-oate or other alkyl ester thereof as the starting steroid, there is produced 3-ethoxy- 9a-tluoro-11fi,21-dihydroxy-3,5,17(20)-pregnatriene.

Substituting other 3-enol ethers of methyl or other alkyl ester of 3-keto-9a-fluoro-l1B-hydroxy-3,5,17(20)-pregnatrine-21-o'ate, e. g., methyl or other alkyl ester of 3- methoxy, 3-propoxy, 3-ethylmercapto, 3-o-methylbenzy1- oxy, 3-allyloxy, or 3-benzyloxy-9a-fluoro-1lp-hydroxy- 3,5,17(20)-pregnatriene-21-oic acid, as starting steroid in the reduction, is productive of the corresponding 3-enol ether of 9a fiuoro 11 3,21 dihydroxy 4,l7(20)-pregnadiene-3-one.

7 Substituting the corresponding 9a-chloro compound for oneof the9a-fiuoro compounds described in Example 12 is'productive of the corresponding 3-enol ether of 90achloro-l1B,2l-dihydroxy-4,17(20) pregnadiene 3 one, e. g., 3-ethoxy-9a-chloro-11/8,21-dihydroxy-3,5,l7(20)- pregnatriene from methyl 3-ethoxy-9a-chloro-ll-hydroxy- 3,5 17 (20) -pregnatriene-2 l-oate.

EXAMPLE 13 9a -flur0-1 1 3,21 -dihydroxy-4,1 7(20) -pregnadiene-3-o ne The crude 3-ethylene glycol ketal of 3a-fluoro-l1fi,21-

dihydroxy-4,17(20)-pregnadiene-3-one, obtained as the distillation residue from the benzene solution obtained in exactly the manner described in Example 9, was dissolved in 35 milliliters of acetone. To the solution was added five milliliters of .a 1.0 N solution of sulfuric acid and the acidic mixture maintained with stirring at about 25 degrees centigrade for six hours. Water was then added tothe mixture. The aqueous mixture was extracted with methylene chloride and the methylene chloride extract then washed with aqueous sodium bicarbonate followed by water. The extract was dried and the solvent distilled at reduced pressure. The residue was dissolved in a mixture of benzene and "methylene chloride and poured over a chromatographic column of fifty grams of Florisil synthetic magnesium silicate. The column was developed with 100 milliliter portions of solvent of the following composition and order: five of Skellysolve B plus 7.5 percent acetone, seven of Skellysolve B plus ten percent acetone, five of Skellysolve B plus fifteen percent acetone, five of Skellysolve B plus twenty percent acetone and one of acetone. The Skellysolve B plus fifteen percent acetone eluates contained 190 milligrams of product. Triturationof this product with ether followed by crystallization from a mixture of ethyl acetate and ether gave fine needles of 9t fluoro-11;8,21-dihydroxy-4,17(20)- pregnadiene-3-one melting at 202.5 to 204 degrees centi' grade and having the analysis below:

Calculated for C H FO F, 5.45. Found: F, 5.55,

Following the procedure described in Example 13, other 3-ketals of 9a-fluoro-11fi,2l-dihydroxy-4,l7(20)- pregnadiene-B-one, e. g., the 3-propylene glycol ketal, 3- trimethylene glycol ketal, 3-butane-1,2-diol ketal, 3-pentane-l,2-diol ketal, 3-pentane-2,4-diol ketal, hexane-1,3- diol ketal, heptane-l,2-diol ketal, octane-1,2-diol' ketal of 9a 'fluoro-l l B,21-dihydroxy-4,17(20) -pregnadiene-3-one, are hydrolyzed to 9a-fluoro-11;3,21-dihydroxy-4,17(2O) pregnadiene-3-one. I

EXAMPLE 14 9u-chl0r0-1Ifi,21-dihydr0xy-4,17(20) -pregnadiene-3-0ne Following the procedure described in Example 13, but substituting a 3-cyclic ketal of 9a-chloro-l1fi,21-dihydroxy-4,17(20)-pregnadiene-3-one, e. g., the 3-ethylene glycol ketal for the corresponding 9a-fluoro compound employed as starting steroid in the reaction described in Example 13, there is thus produced 9a-Chl01'O-11fl,21- dihydroxy-4,l7(20)-pregnadiene-3 one as the hydrolysis product.

Following the procedure described in Example 13, but substituting the S-enamine or 3-eno1 ether of 9a-fiuoro- 1113,21-dihydroxy-4,17(20)-pregnadiene-3-one, e. g., 3- pyrrolidyl-9a-fiuoro-11e,21-dihydroxy-3,5,17(20). .pregnatriene or 3-ethoxy-9a-fiuoro-11p,21-dihydroxy-3,5,l7 (ZOPpregnatriene, there is similarly produced 9a-fluoro- 1lB,2l-dihydroxy-4,l7(20)-pregnadiene-3-one. A 3-enamine or 3-enol ether of 9a-chloro-l1fl,21-dihydroxy-4,l7 (20)-pregnadiene-3-one, e. g., 3-pyrrolidyl-9a-chloro-l1B, 21-dihydroxy-3,5,l7(20)-pregnatriene or 3-ethoxy-9uchloro-l16,21-dihydroxy-3,5,17(20)-pregnatriene is hydrolized to a 9a-chloro-11B,21-dihydroxy-4,17(20)-pregnadiene-S-one. The hydrolyzing agent for the enamine is preferably an aqueous base, e. g., sodium or potassium bicarbonate or sodium hydroxide.

EXAMPLE 15 9oc-flzl0r0-1 1 B-lzydroxy-Zl -acetoxy-4,1 7 20) -pregnadienewashed successively with ice cold dilute aqueous hydro-' Crude 9u-fiuoro-11fi,21 dihydroxy 4,17(20) pregnadiene-3-one, obtained from the chromatographic column of a reaction performed inexactly the manner described in Example 13, was dissolved in a mixture of five milliliters of acetic anhydride and five milliliters of pyridinei The solution was maintained at about 25 degrees centigrade for about sixteen hours and then poured into a mixture of ice and water. The gummy precipitate-was extracted with methylene chloride and the extract then chloric acid, cold aqueous sodium bicarbonate and finally with cold water. The methylene chloride solution, after drying, was poured over a chromatographic column of 75 grams of Florisil synthetic magnesium silicate.

,by known other procedures for the esterification of a steroidal hydroxy' group, e. g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester -by ester exchange, acid in the presence of an esteri fication' catalyst, etc., 9a-fiuoro-11p,2l-dihydroxy-4,l7-

( 20)-pregnadiene-3-one is -similarly converted to other The column was developed with milliliter portions of} selected esterifying agent.

21-esters thereof. Examples of 9a-fluoro-11p-hydroxy- 21-acyloxy-4, 1 7 (20) -p,regnadiene-3-one prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2- methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acyclic acid, e. g., SB-hydroxycholanic, Bfi-hydroxyetiocholanic cyclopropylideneacetic, a cycloaliphatic acid, e. g., cyclopentylformic, cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl or alkaryl acid, e; g., benzoic, 2,3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6- trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic, 3- methyl-a-naphthoic, an aralkyl acid, e. g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid, e. g., succinic, glutaric, u-methylglutaric, p-methylglutaric, fi,B-dimethylglutaric, adipic, pimelic, suberic, a hydroxyacid, e. g., glycolic, lactic, citric, tartaric d-maleic, d-glyceric, mannoic, gluconic, salicylic, an aminoacid, e. g., glycine, diglycollamic, triglycollarnic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, paraaminobenzoic, other hetero-substituted acids, e. g., ethylmercaptoacetic, benxylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, a-naphthoxyacetic, B- pyrrolidylpropionic, carbamic acids, e. g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allophanic, or a heterocyclic acid, e. g., B-furylcarboxylic, N-methylpyrrolidyl-2-carboxylic, o;- picolinic, indole-2-carboxylic, 6-hydroxyindolyl-3-acetic, N-methylmorpholyl-Z-carboxylic, lysergic, pyrrolyl-2carboxylic, or other acyl acid.

Alternatively, the ZI-hydroxy group of 9oc-fiu0rQ- 1lfl,2l-dihydroxy-4,17(20)-pregnadiene-3-one can be con verted to another Ill-derivative leaving the remainder of the molecule unchanged. Examples of such 21- derivatives are 2l-ethers, e. g., 2lmethoxy, ethoxy, benzyloxy, propoxy, a-tetrahydropyranyloxy, (,B-carbethoxy- ,6-cyano)ethyleneoxy, fi,B-dicarbethoxyethenyloxy, fl-ketocyclohexenyloxy, ,8-trichloro-m-acetylethoxy, chlorornethoxy, dirnethylmethoxy, diethylmethoxy, dimethylethoxy, diethylethoxy, 21-thioesters, e. g., acetylmercapto, B-cyclopentylpropionylmercapto, triethylacetylmercapto, trimethylacetylmercapto, propionylmercapto, 21-thione esters, e. g., thioacetyloxy, thiopropionyloxy, thio-fl-cyclopentylpropionyloxy, thiotriethylacetyloxy, thiotrimethylacetyloxy, imido derivatives of acetyl esters, e. g. acetimido-oxy, 21-esters of mineral acids, e. g., 2l-phosphate, 2l-sulfonate, 21-sulfinate, 21-methylphosphate, 21-methylsulfonate, 21-methylsulfinate, ZI-bromo, fluoro or 21.- chloro, esters or" the carbonic acids, "e. g., 21 -carbonate, 2l-(triethoxy)methoxy, 21-sulfonyloxy, e. g., 21-paratoluenesulfonyloxy, etc, r i r EXAMPLE 16 chloro-llB-hydroxy-Zl acetoxy-4,17(20)-pregnadiene-3 one.

Similarly, other 9a-chloro 11p-hydroxy-21-acyloxy-4,- 17(20)-pregnadiene-3-ones are. prepared by the reaction of 9wchloro-1113,21-dihydroxy- 4,17 (20)-pregnadiene 3- one with the acid chloride of, acidarrhydrideofpor acid named in. Example 15 or the paragraph following,under the appropriate esterification conditions, wherein the acyl radical of the ,21-acyloxy, group is the acyl radical of the Approximately milligrams of impure 9a-fluorol 1fi-hydroxy2 1-acetoxy-4, 17 (20 -pregnadiene-3-one, ob tained from the chromatographic column from a reaction performed in exactly the manner described in Example 14, was dissolved in eight milliliters of dry tertiary butyl alcohol containing one milliliter of dry pyridine. The solution was mixed at room temperature with stirring with 0.6 milliliter of a solution of 0.165 N( solution. of N-methylmorpholineoxide peroxide in dry tertiary butyl alcohol. To this mixture was added five milligrams of osmium tetroxide and the solution stirred for 4.5 hours at about 25 degrees Centigrade. Aqueous sodium sulfite was then added and the mixture extracted with methylene chloride. The extract was washed with Water, dried and the solvent distilled. The distillation residue was dissolved in benzene and poured over a chromatographic column of fifteen grams of Florisil synthetic magnesium silicate. The column was developed with fifty milliliter portions of solvents of the following compositionand order: five of Skellysolve B plus 7.5 percent acetone, five of Skellysolve B plus ten percent acetone, five of, Skellysolve B plus fifteen percent acetone, three of Skellysolve B plus twenty percent acetone and one of acetone. The Skellysolve B plus fifteen percent acetone elu'ates were distilled to dryness leaving 47 milligrams of 9a-fluoro- 1 1B,17a-dihydroxy-21-acetoXy-4-pregnene-3,20'dione (9 fluorohydrocortisone acetate) melting at to 200 degrees Centigrade.

Following the procedure described in Example 17, or employing one of the other oxidizing agents described herein, other 9a-fiuoro-1 IB-hydroxy-Z1-acyloxy-4,17(2(1)- pregnadiene-3-ones (VI) are converted to the corresponding 9a-fluoro-1 15,17a-dihydr0xy-2l-acyloxy4-pregnene- 3,20-diones (VII) wherein the acyl group of the starting steroid and the reaction product is the acyl radical of, for

example a lower-aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2- methylbutyric, B-ethylbutyric, hexanoic, di-ethylacetic, triethyiacetigheptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acyclic acid, e. g., 3B-hydroxycholanic, 3fi-hydroxyetiocholanic, cyclopropylideneacetic, a cycloaliphatic acid,- e. g., cyclopentylformic, cyclopentyl: acetic, ,6 cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fi-cyclohexylpropionic, an aryl or alkaryl acid, e. g., benzoic, 2,3 or 4-methylbenzoic, 2,3-, 2,4-, 2,5-,. 2,6-,

3,4- and 3,5 dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-triethylacetic, a-naphthoic, .3-methyla-naphthoic, an aralkyl acid, e. g., phenylacetic, phenylw propionic, diphenylacetic, triphenylacetic, a dibasic acid, e. g., succinic,glutartic, u-methylglutaric, ,fi-methylglw taric, [3,B-dimcthylglutaric, adipic, pimelic suberic, a hydroxy acid, e. g., glycolic, lactic, citric, tartaric, d maleic, d-glyceric, mannonic, gluconic, salicylic, an raminoacid, e. g. glycine, diglycollamic, triglycollamic, methylglycine, .dimethylglycine, diethylglycine, para-aminosalicylic, para: aminobenzoic, other hetero-substituted acids, e. g., ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, ChlOl'O-e acetic, fluoroacetic, trichloroac'etic, glycolic, 2,3,4 trimethoxybenzoic,

trifluoroacetic, -thioa-napthoxyacetic, 8-

pyrrolidylpropionic, carbarnic acids e. g., carbarnic acid,

phenylcarbamic, n-butylcarbamic, dimethylcarba mic, diethylcarbamic, allophanic, or a heterocyclic acid, e. g., B- furylcarboxylic, Nmethylpyrrolidyl-2-carboxylic, a-picclinic, indole-Z-carboxylic, 6-hydroxyindo1yl-3-acetic,' N-

methylrnorpholyl 2 carboxylic, lysergic, pyrrolyl-Z-carboxylic, or other acyl acid. a

In some instances, the acyl group will 'be'atfe'cted} p the hydroxylating and/or oxidizing agent, in which nstances, the acyl radical of the reaction product differ from thatof the starting material, is. g.,.when th aga 1 23 acyl group is the acyl radical of an unsaturated acid, e. g., 3-butenoic acid.

Similarly, oxidative hydroxylation of the corresponding 21- derivative of 9a fluoro 11fi,21-dihydroxy-4,17(20)- pregnadiene-S-one according to one of the methods described herein is productive of 9a-fluoro-11B,17d-dihydroxy 21 substituted-4-pregnene-3,20-dione wherein the 2l-substitution is a 21-ether, e. g., ZI-methoxy, ethoxy, benzyloxy, propoxy, u-tetrahydropyranyloxy, (fl-carbethoxy-fl-cyano)methyleneoxy, {3,[3 dicarbethoxyethenyloxy, '18 ketocyclohexenyloxy, (B trichloro oz acetyl)ethoxy, chloromethoxy, dimethylrnethoxy, diethymethoxy, dimethylethoxy, diethylethoxy, a 21-thioester, e. g., acetylmercapto, fi-cyclopentylpropionylmercapto, triethylacetylmercapto, trimethylacetylmercapto, propionylmercapto, a 21- thione ester, 'e. g., thioacetyloxy, thiopropionyloxy, thio-flcyclopentylpropionyloxy, thiotriethylacetyloxy, thiotrimethylacetyloxy, an imido derivative'of an acyl ester, e. g., acetimido-oxy, a 21-ester of a mineral acid, e. g., phosphate, phosphate, sulfonate, sulfinate, .methylphosphate, methylsulfone, methylsulfinate, bromo, fluoro, chloro, or, for example, the ZI-carbonate ester, 21-(triethoxy)methoxy ester or 21-sulfonyloxy ester, e. g., 21-para-toluenesulfonate.

EXAMPLE 18 dihydroxy 21 acetoxy 4 preg- 9a 5 chloro 1113,17u

nene-3,20-di0ne EXAMPLE 19 dihydroxy 21 acetoxy 4 preg- 9... fluoro 2 11pm nene-3,20-dione To a solution of 1.116 grams (3.0 millimoles) of 90cfluoro 11.13 hydroxy 21-acetoxy-4,17(20) -pregnadiene- 3-one dissolved in sixty milliliters of tertiary butyl alcohol and 1.5 milliliters of pyridine is added, at 25 degrees centigrade, five milliliters of tertiary butyl alcohol containing 11.1 milligrams (0.044 millirnole) of osmium tetroxide and 0.2 milliliter (0.11 inillimole) of water. To the solution is then added*2.4 grams (7.5 mil-limoles) of phenyliodosoacetate, which completely dissolves within twenty minutes. When the reaction is substantially complete, twenty milliliters of Water is added to the reaction mixture and then distilled at reduced pressure to a volume of about twenty milliliters. An additional twenty milliliters1of .water is added to the residue and the mixture thoroughly extracted with ethylene dichloride. The steroidalportion of the extract consists mainly of 90a fluoro -1 1}3,'17a dihydroxy 21 acetoxy 4- pregnene-3,20'dione. 4 v e EXAMPLE 20 'Qa-fluoro-l113,17d4dihydroxy2I-acetoxy-4-pregncite-3,20- t i dione To a solution of 744 milligrams (2.0 millimoles) of 90: fluoro llfl hydroxy 21 acetoxy 4,17(20)- pregnadiene-3 one in thirtyrnilliliters of tertiary butyl alcohol is added one milliliterv of pyridine and 25 milligrams; (0.1 millirnole) of osmium tetroxide in eight milliliters of tertiary butyl alcohol.v To the resulting solution is added 8. 36 milliliters (5.0 millimoles'lof an QiQ P hy rogen peroxide in sodium dried about fifteen milliliters by distillation at a pressure of.

about fifty milliliters mercury absolute and the resulting concentrate then extracted with methylene chloride. The methylene chloride extract is dried. The steroidal product consists mainly 'of 9a-fiuoro-115,17a-dihydroxy-21- acetoxy-4-pregnene-3,20-dione. The glycol by-product is 9a fluoro l1f3,l7o,20 trihydroxy 21 acetoxy 4 pregnene-3-one.

, It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds showrl and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. The process which comprises opening the oxido group of 3-kcto-9:11-,8-oxido-4,17(20)-pregnadiene-2loic acid alkyl ester with a hydrohalic acid selected from the group consisting of hydrochloric acid and hydrofluoric acid, under substantially anhydrous conditions, to produce 3 keto 9a halo 11B hydroxy 4,17(20)- pregnadiene-Zl-oic acid alkyl ester.

2. The process of claim 1 wherein the hydrohalic acid is hydrofluoric acid.

3. The process of claim lwherein the hydrohalic acid is hydrofluoric acid and the starting steroid is 3-keto-9: ll- [3-oxido-4, l 7 (20) -pregnadiene-2 l-oic acid methyl ester.

4. The process of claim 1 wherein the hydrohalic acid is hydrochloric acid and the starting steroid is 3-keto- 9:1l-fl-oxidot,17(20)-pregnadiene-21-oic acid methyl ester.

5. 3 keto 9a halo 1113 hydroxy 417(20) pregnadiene-Zl-oic acid lower-alkyl ester represented by the following formula:

' to 127 inclusive.

6. A lower-alkyl '3 keto c fiuoro 11B hydroxy-f 4,l7(20)-pregnadiene-2l-oate represented by the follow ing formula:

(d O O -lower-alkyl r 7. Methyl 3 a keto 9a fluoro 7 hydroxy-i 11p hydroxy- 4,17(20)-pregnadiene-21-oate.

amass 10. Ethyl 3 keto 9oc--ch101O 1113 hydroxy- 4,17(20) pregnadiene-Zhoate. v

1 1. Methyl 3 keto 90c brorno 11,8 hydroxy 4, 17 (20) -pregnadiene-2 l-oate.

{12.The process which comprises the steps of opening the oxido group of- 3-keto-9:1l-fi oxido-4,17(20)-pregnadiene-21-oic acid alkyl ester with a hydrohalic acid selected from the group consisting of hydrochloric acid and hydrofluoric acid,.under substantially anhydrous, conditions, to produce 3rketo-9a-halo-11fi-hydroxy-4,17(20)- pregnaditene-Zl-oieacid alkyl ester wherein the 9ot-halo group is a halogen having an atomic weight from.19 to 36, inclusive; and converting the 3-keto group of the thus-produced 9a-halo steroid to a reduction stable ketonioderivative selected from the group consisting of 3-enol ether, 3-ketal and. 3-enamine, to. produce 3-keto- 9a,- halo 1113 hydroxy 4,l7(20) pregnadiene 21- oicacid alkyl ester, protected at the 3-position from reduction.

13'; The process. of claim l2'wherein the hydrohalic acid is hydrofluoric acid and the reduction stable ketonic derivative is a 3-ketal.

14. The process of claim 12, wherein the hydrohalic acidis hydrofluoric acid and the reduction stable ketonic derivative is the 3-.ethylene glycol ketal. l 15. The process of claim 12 wherein the hydrohalic acid. is hydrofluoric acid, the reduction stable ketonic derivative. is the 3.-ethylene glycol ketaLand the starting steroid is methyl 3-ket0t-9:ll-fl-oxidol,17(2O) -pregna diene-Zl-oate.

p 16. The processof claim IZWhereinthe hydrohalic acid is hydrochloric acid, the reduction stable ketohicde: rivative'is the B-ethyl'ene glycol ketal, and. the starting diene-ZI-oate.

17. 3-ketalized loWer-alkyl 3-keto-9a-halo-llfi-hydroxy- 4,1?(20)-pregnadiene-21-oates represented by the follow ing formula:

(I? O -wer-alkyl wherein R and R are each selected frornthe group con sisting of hydrogen and lower-alkyl, n is a whole numbe; from one to, two, and the divalent ketal radical. con tains less: than nin e carbon atoms, and X is a halogen having anatomicf weight from.;19 K11 5, inclusive. l8. B-ketalized lower alkyl 3 k6tO-9Ot-haIo-1IB hYdIOXY 4,, 7(20 :pregnadiene-Zboates representecl by the followingtormulafl it C O O -l0wer-alky1 CHO wherein X 'is a halogen haying an atomic weight from 26 t "19. 3-k etalized lower-alkyl 3 ke to-9a-fluoro-ilfl hy droxy-4,17(20) pregnadiene-21-oates represented by the following formula:

wherein n is a whole number from one to two. r t 20. The S-ethylene glycol ketal of methyl 3-keto-9ufluoro-l1fl-hydroxy-4,17(20)-pregnadiene-21-oate. 21. The 3-ethylene. glycol ketal of ethyl 3-k6t090tfluoro-l 1,8-hydroxy-4,17(20)-pregnadiene-21-oate.

22. The. 3-ethylene glycol ketal of methyl 3-l et o-9 achloro-l lfl-hydroxy-4,17(20)-pregnadiene-21-oate.

23. The 3-ethylene glycol ketal of ethyl 3-k6lO-9achloro-l 1/3-hydroxy-4,17 20)-pregnadiene-2l-oate.

24. The process which comprises the steps of opening the oxido group of 3-keto-9 :l1-B-oxido-4,l7(20)-pregnadiene-2l-oic acid alkyl ester with a hydrohalic acid selected from the group consisting of hydrochloric acid and hydrofluoric acid, under substantially anhydrous conditions, to produce 3-keto-9u-halo-llBhydroXy-4,l7(20)- pregnadiene-Zl-oic acid alkyl ester; converting the 3 -keto group of the thus-produced 9a-halo steroid to a reduction stable ketonic derivative selected from the group consisting of 3-enol others, 3-ketals and 3-enarnines to produce 3-keto-9u-halo-l lfl-hydroxy-4, 17(20) pregnadiene-Zl-oic acid alkyl ester, protected at the 3-position from reduction; and, reducing the thus-protected 9et-halo steroid with lithium aluminum hydride to produce halo-11,6,21-dihydroXy-4,17(20)-pregnadiene-3 one, protected at the 3-position from reduction.

25. The process of claim 24- wherein the hydrohalic acid is hydrofluoric acid and, the reduction stable ke'tonic derivative is a 3-ketal.

1 26; The process: of claim 24, wherein the hydrohalic acid is hydrofluoric acid and the reduction stableketonic derivative is the. SI-ethylene glycol' ketali l T27. The! process of claim 24 wherein the hydrohalic acidis hydrofluoric acid, the. reduction stable. ketonic derivative is the 3-ethylene glycolketa-l, and the starting steroid is. methyl 3-keto-9:1l-fi-oxido44,l7(20)-pregna diene-Zl-oate. r

281 The process of claim 2 4 wh'erein the hydrohalic acidisl hydrochloric acid, the reduction stable ketonic derivative is the 3-et hyl'ene glycol ketal, and the starting steroid is methyl 3=keto-9: 11-;9-oxido-4, l7 20) -pregnadiene-Zl-oate.

29. 3-ketalized-9a-halo- 11fl,2.1-dihydroxy- 4,1-7(20)- pregnadieneJ-onerepresented by the following formula:

oupconsisting tains less than nine carbon atoms and X is a halogen having an atomic weight from 19 to 36, inclusive.

30. 3-ketalized-9ot-fluoro-11,8,21-dihydroxy 4,17(20)- pregnadiene-3-one represented by the following formula:

wherein n is a whole number from one to two, inclusive.

31. The 3-ethylene glycol ketal of 9a-chloro-11;3,2l-dihydroxy-4, 1 7 (20) -pregnadiene-3-one.

32. The 3-ethylene glycol ketal of 9oc-fill01O-l1fl,21-dihydroxy-4, l 7 (20') -pregnadiene-3 -one.

33. The process which comprises the steps-of opening the oxido group of v3-keto-9:ll-/8-oxido-4,17(20)-pregnadiene-Zl-oic acid alkyl ester with a hydrohalic acid selected from the group consisting of hydrochloric acid and hydrofluoric acid, under substantially anhydrous conditions, to produce 3-keto-9a-halo-1lp-hydroxy- 4,17(20)-pregnadiene-21-oic acid alkyl ester; converting the 3-keto group of the thus-produced 9u-halo steroid to a reduction stable ketonic derivative selected from the group consisting of 3-enol ethers, 3-ketals and 3-enamines, to produce 3-keto-9u-halo-11fi-hydroxy-4,17(20)- pregnadiene-Zl-oic acid alkyl ester, protected at the 3- position from reduction; reducing the thus-protected 9ahalo steroid with lithium aluminum hydride to produce 9a-hal0-11;3,21 dihydroxy-4,17(20)-pregnadiene-3-one, protected at the 3-position from reduction; hydrolyzing the protecting group at the 3-position of the thus-pro duced 9a-halo-llj3,2l-dihydroxy steroid with a hydrolyzing agent to produce 90: halo 11B,21-dihydroxy'- 4,17(20)-pregnadiene-3-one.

34. The process of claim 33 wherein the hydrohalic acid is hydrofluoric acid and the reduction stable ketonic derivative is a 3-ketal.

35. The process of claim 33 wherein the hydrohalic acid is hydrofluoric acid and the reduction stable ketonic derivative is the S-ethylene glycol ketal.

36. The process of claim 33 wherein the hydrohalic acid is hydrofluoric acid, the reduction stable ketonic derivative is the 3-ethylene glycol ketal, and the starting steroid is methyl 3-keto-9:11-B-oxido-4,17(20)-pregnadiene-Zl-oate.

.37. The process of claim 33 wherein the hydrohalic acid is hydrochloric acid, thereduction stable ketonic derivative is the 3-ethylene glycol ketal, and the starting 40. 9u-fiuoro-11fi,21-dihydroxy 4,17(20) pregnadiene-3-one.

-41. The process which comprises the steps of opening the oxido group of 3-keto-9:1l-fi-oxido-4,l7(2())-preg nadiene-Zl-oic acid alkyl ester with a hydroha'lic acid selected from the group consisting of hydrochloric acid and hydrofluoric acid, under substantially anhydrous conditions, to produce 3-keto-9a-halo-1lfi-hydroxy- 4,17 (20)-pregnadiene-2l-oic acid alkyl ester; converting the 3-keto group of the thus-produced 9a-halo steroid to a reduction stable ketonic derivative selected from the group consisting of 3-enol ethers, 3-ketals and 3-enamines, to produce 3-keto-9tx-halo-l lB-hydroxy-4,l7(20)- pregnadiene-Zl-oic acid alkyl ester, protected at the 3- positionfrom reduction; reducing the thus-protected 9ahalo steroid with lithium aluminum hydride to produce 9a-halo-1118,21-dihydroxy-4,17(20) pregnadiene-3-one; protected at the 3-position from reduction; hydrolyzing the protecting group at the 3-position of the thus-produced 9oc-halo-llfl,2l-dihydroxy steroid with a hydrolyzing agent to produce 9a-halo-l1p,2l-dihydroxy-4,17(20)- pregnadiene-S-one; and esterifying the thus-produced 9ahalo-l1p,21-dihydroxy-4,17(20) pregnadiene-3-one to produce a 21-mono ester thereof.

42. The process of claim 41 wherein the hydrohalic acid is hydrofluoric acid and the reduction stable ketonic derivative is a 3-ketal. a

43. The process of claim 41 wherein the hydrohalic acid is hydrofluoric acid and the reduction stable ketonic derivative is the'3-ethylene glycol ketal;

44. The process of claim 41 wherein the hydrohalic acid is hydrofluoric acid, the reduction stable ketouic derivative is the 3-ethylene glycol ketal, and the esterity ing agent is acetic anhydride, to produce 3-keto-9a-fluoro- 1 1,8-hydroxy-21-acetoxy-4, 17 (20) -pregnadiene-3-one.

45. The process of claim 41 wherein the hydrohalic acid is hydrochloric acid, the reduction stable ketonic derivative is the 3-ethylene glycol ketal and the esterifying agent is acetic anhydride, to produce 9u'-chloro-ll;8- hydroxy-2l-acetoxy-4,17(20)-pregnadiene-3-one.

46. 9m-halo-1lfi-hydroxy-Zl-acyloxy 4,17(20)-pregnadiene-3-one represented by the following formula:

steroid is methyl 3 keto-9z11 B oxido -4,l7(20)pregnadiene-21-oate.

38. 9ot-halo-l1p,21-dihydroxy-4;17 (20) 'pregnadiene- S one represented by the following formula:

OHr-OH wherein X is a halogen having an atomic weight from 19 to 36, inclusive, Ac is the acyl radical of a hydroc'ar hon carboxylic acid having up to twelve carbon atoms," inclusive. -47. 9a-fluoro-1lp-hydroxy-Zl-acyloxy 4,17(20)-preg{ nadiene-3-one represented by the following formula:

; boxylic acid having up to twelve carbon atoms, inclusive:

48. 9oc-Ch10l'0 11p hydroxy-Zl-acyloxy 4,17 (20)- pregnadiene-3-one represented by the following formula:

HO T 01 50. 9u-chioro 11,5 hydroxy-Zl-acetoxy 4,17(20)- pregnadiene-B-one.

51. The process which comprises hydrolyzi'ng 9a-halo- 1 1;8,21-dihydroxy-4,17(20) -pregnadiene-3-one, protected at the 3-position by a member of the group consisting of the 3-enol ether, the 3-ketal and I i-enamine, with a hydrolyzing agent to produce 9u-halo-11fi,21-dihydroxy- 4,17(20)-pregnadiene-3-one and es'terifying with an esterifying agent the thus-produced 9a-halo-11,B,21-dihydroxy-4,17(20)-pregnadiene-3-one to produce a 21- ester thereof.

52. The process of claim 51 wherein the esterifying agent is the anhydride of a hydrocarbon carboxylic acid containing up to twelve carbon atoms, inclusive.

53. The process of claim 51 wherein the 9a-halo- 11fi,21-dihydroxy-4,17(20) pregnadiene-B-one is protected at the 3-position by an enamine group, and the halogen is fluorine.

No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,875,200 February 24, 1959 John A. Hogg et 21.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 24: to 34, Formulas VIII and XII should appear as shown below instead of as in the patent- CH CH CH3 (300R O=O CE column 9, line 65, for 11a-hydroxyread 11,B-hydroxy--; column 20, line 36, for to a 9w read -to 9a- Signed and sealed this 21st day of July 1959.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Atteting Ofiiaer. G'onwnissioner of Patents. 

1. THE PROCESS WHICH COMPRISES OPENING THE OXIDO GROUP OF 3-KETO-9:11-B-OXIDO-4,17(20)-PREGNADIENE-21OIC ACID ALKYL ESTER WITH A HYDROHALIC ACID SELECTED FROM THE GROUP CONSISTING OF HYDROCHLORIC ACID AND HYDROFLUORIC ACID, UNDER SUBSTANTIALLY ANHYDROUS CONDITIONS, TO PRODUCE 3 - KETO - 9A - HALO - 11B - HYDROXY - 4,17(20)PREGNADIENE-21-OIC ACID ALKYL ESTER.
 5. 3 - KETO - 9A - HALO - 11B - HYDROXY - 4,17(20) - PREGNADIENE-21-OIC ACID LOWER ALKYL ESTER REPRESENTED BY THE FOLLOWING FORMULA: 